Generally, transdermal drug delivery systems employ a medicated device or patch which is affixed to the skin of a patient. The patch allows a medicinal compound contained within the patch to be absorbed through the skin layers and into the patient's blood stream. Transdermal drug delivery reduces the pain associated with drug injections and intravenous drug administration, as well as the risk of infection associated with these techniques. Transdermal drug delivery also avoids gastrointestinal metabolism of administered drugs, reduces the elimination of drugs by the liver, and provides a sustained release of the administered drug. Transdermal drug delivery also enhances patient compliance with a drug regimen because of the relative ease of administration and the sustained release of the drug.
Many medicinal compounds are not suitable for administration via known transdermal drug delivery systems since they are absorbed with difficulty through the skin due to the molecular size of the drug or to other bioadhesion properties of the drug. In these cases, when transdermal drug delivery is attempted, the drug may be found pooling on the outer surface of the skin and not permeating through the skin into the blood stream. Once such example is insulin, which has been found difficult to administer by means of transdermal drug delivery.
Some of the most critically needed medications are currently administered either by injection or oral dosage forms, which can have several drawbacks. In particular, chemotherapeutic agents are administered in increased dosages because of their need to survive degradation in the gastrointestinal tract. Many critical treatments for AIDS require a cocktail of drugs taken orally in solid dosage forms, several times a day to be effective. These medications are not suitable for administration via known transdermal drug delivery system because of the extensive dosing requirement, as well as the inability of the drug molecule to remain stable in a transdermal form. Moreover, the unsuitability of many drugs for conventional transdermal transfer may be due to low bioabsorbance of the drug across the skin layers.
Generally, conventional transdermal drug delivery methods have been found suitable only for low molecular weight medications such as nitroglycerin for alleviating angina, nicotine for smoking cessation regimens, and estradiol for estrogen replacement in post-menopausal women. Larger molecular medications such as insulin (a polypeptide for the treatment of diabetes), erythropoietin (used to treat severe anemia) and gamma-interferon (used to boost the immune systems cancer fighting ability) are all compounds not normally effective when used with conventional transdermal drug delivery methods.
However, the use of energy, such as ultrasonic energy, may be used to enhance the transdermal delivery of certain drugs. While these terms “ultrasound”and “ultrasonic” as used herein have their ordinary meaning, at least one source has defined “ultrasound” as mechanical pressure waves with frequencies above 20 kHz, H. Lutz et al., Manual of Ultrasound 3-12 (1984). Ultrasound may be generated by vibrating a piezoelectric crystal or other electromechanical element by passing an alternating current through the material. The use of ultrasound to increase the permeability of the skin to drug molecules has been termed sonophoresis or phonophoresis.
Previously described methods for using ultrasound to enhance transdermal drug delivery required the use in a clinical ultrasonic delivery setting, such as a physician's office, hospital or clinic. Moreover, the time for delivery of measurable amounts into human skin using these methods ranged from 10 minutes to 24 hours. In this case, the use of ultrasound-transdermal drug delivery treatment may be actually less desirable from a patient administration standpoint than a simple injection. This method is undesirable because of the need for the patient to visit the clinical setting and to remain on a treatment table while the ultrasound treatment is used to deliver the drug.
While the use of certain ultrasonic frequencies for the enhancing delivery of certain drugs in certain applications is known, results in such applications have been largely disappointing. In many cases the drug delivery pathway utilized enabled initial quantities of a drug to permeate the skin, but as longer periods of ultrasound were applied to the same location on the skin the delivery rate dropped off or was reduced to zero.
The exposure to ultrasound has been either continuous or pulsed to reduce heating of biological membranes. The depth of penetration of ultrasonic energy into living soft tissue is inversely proportional to the frequency, thus high frequencies have been suggested to improve drug penetration through the skin by concentrating the effect in the outermost skin layer, the stratum corneum. Pharmaceutical agents under sonic transdermal delivery may require variable frequencies and intensities in order to deliver therapeutic quantities of drugs to patients. Variables such as fat content and mass of a particular patient's tissue, through which the drug will be delivered, may vary the frequency and intensity requirements to obtain an effective dosing regimen.
Portable programmable devices and methods for ultrasonically enhancing substance delivery through a surface of a subject have not been disclosed. Because of the inefficiencies and lack of safety of the previous ultrasonic methods, no useful device has been proposed for the transdermal delivery of drugs with an ultrasonic assist.
Little effort has in the past been focused upon the design of a transdermal patch suitable for ultrasonic drug transport. The use of an ultrasonic applicator or sonicator applied to skin tissue has conventionally been employed with a pool of a target drug laying under the tip of the transducer and laying upon the skin surface. This method of ultrasonic drug delivery is not believed to be feasible in a commercial application. Other examples in which the skin is pre-sonicated and then a patch is placed over the sonicated skin area employ a passive drug delivery based upon the concept of induced increased permeability as effected by the ultrasonic transmission. This also is commercially non-feasible because of the length of time needed to pre-sonicate the skin and other factors.
In view of the foregoing problems and/or deficiencies, the development of a device for safely enhancing the permeability of the skin for noninvasive drug delivery in a more rapid time frame would be a significant advancement in the art. It would be another significant advancement in the art to provide an ultrasonic programmable device and method that can be used with a drug-containing patch. In addition, patient mobility, coupled with sustained release of a broad range of drugs, until now, has remained an elusive goal of transdermal drug delivery devices. Thus, the design of a suitable transdermal patch to accommodate an active ultrasonic transdermal delivery method is helpful to achieving a commercial ultrasonic drug delivery device.